scholarly journals Heart regeneration: beyond new muscle and vessels

2021 ◽  
Author(s):  
Judy R Sayers ◽  
Paul R Riley
Keyword(s):  
Heart Development ◽  
Cell Function ◽  
Cell Types ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiovascular Tissue ◽  
Function Calls ◽  
Heart Muscle Cells ◽  
System Cell ◽  
Heart Injury

Abstract The most striking consequence of a heart attack is the loss of billions of heart muscle cells, alongside damage to the associated vasculature. The lost cardiovascular tissue is replaced by scar formation, which is non-functional and results in pathological remodelling of the heart and ultimately heart failure. It is, therefore, unsurprising that the heart regeneration field has centred efforts to generate new muscle and blood vessels through targeting cardiomyocyte proliferation and angiogenesis following injury. However, combined insights from embryological studies and regenerative models, alongside the adoption of -omics technology, highlight the extensive heterogeneity of cell types within the forming or re-forming heart and the significant crosstalk arising from non-muscle and non-vessel cells. In this review, we focus on the roles of fibroblasts, immune, conduction system, and nervous system cell populations during heart development and we consider the latest evidence supporting a function for these diverse lineages in contributing to regeneration following heart injury. We suggest that the emerging picture of neurologically, immunologically, and electrically coupled cell function calls for a wider-ranging combinatorial approach to heart regeneration.

scholarly journals A Systematic Exposition of Methods used for Quantification of Heart Regeneration after Apex Resection in Zebrafish

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 548 ◽  
Author(s):  
Helene Juul Belling ◽  
Wolfgang Hofmeister ◽  
Ditte Caroline Andersen
Keyword(s):  
Human Heart ◽  
Quantitative Methods ◽  
Heart Function ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Ability To Regenerate ◽  
Specific Proteins ◽  
Heart Injury ◽  
Whole Heart ◽  
Study Designs

Myocardial infarction (MI) is a worldwide condition that affects millions of people. This is mainly caused by the adult human heart lacking the ability to regenerate upon injury, whereas zebrafish have the capacity through cardiomyocyte proliferation to fully regenerate the heart following injury such as apex resection (AR). But a systematic overview of the methods used to evidence heart regrowth and regeneration in the zebrafish is lacking. Herein, we conducted a systematical search in Embase and Pubmed for studies on heart regeneration in the zebrafish following injury and identified 47 AR studies meeting the inclusion criteria. Overall, three different methods were used to assess heart regeneration in zebrafish AR hearts. 45 out of 47 studies performed qualitative (37) and quantitative (8) histology, whereas immunohistochemistry for various cell cycle markers combined with cardiomyocyte specific proteins was used in 34 out of 47 studies to determine cardiomyocyte proliferation qualitatively (6 studies) or quantitatively (28 studies). For both methods, analysis was based on selected heart sections and not the whole heart, which may bias interpretations. Likewise, interstudy comparison of reported cardiomyocyte proliferation indexes seems complicated by distinct study designs and reporting manners. Finally, six studies performed functional analysis to determine heart function, a hallmark of human heart injury after MI. In conclusion, our data implies that future studies should consider more quantitative methods eventually taking the 3D of the zebrafish heart into consideration when evidencing myocardial regrowth after AR. Furthermore, standardized guidelines for reporting cardiomyocyte proliferation and sham surgery details may be considered to enable inter study comparisons and robustly determine the effect of given genes on the process of heart regeneration.

Abstract 348: Interleukin 13 is Required for Neonatal Heart Regeneration

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Caitlin C O’Meara ◽  
Dana Murphy ◽  
Angela Lemke ◽  
Michael J Flister
Keyword(s):  
Cell Cycle ◽  
Knockout Mice ◽  
Heart Development ◽  
Contradictory Result ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Growth ◽  
Interleukin 13 ◽  
Neonatal Heart

Shortly after birth neonatal mice can fully regenerate their hearts, but this potential is lost in the first week of life. Cell cycle entry of existing cardiomyocytes is thought to be an essential mechanism enabling neonatal mouse heart regeneration. In previous studies we found that the cytokine interleukin 13 (IL13) was a an upstream regulator of differentially expressed gene networks during neonatal heart regeneration and stimulated cell cycle activity of cultured rat cardiomyocytes, suggesting that this factor might be important in neonatal heart regeneration in vivo . In the present study, we subjected wildtype and IL13 knockout mice to ventricular apical resection at one day of age and assessed heart regeneration 21 days post resection (dpr). Compared to wildtype controls, IL13 knockout mice failed to regenerate their hearts as determined by extensive scar formation at the ventricular apex. To gain insight into the mechanism of impaired regeneration, we quantified cardiomyocyte proliferation and expression of macrophage markers at 7 dpr. We found no difference in gene expression of macrophage markers in IL13 knockout mice compared to wildtype. Interestingly, IL13 knockout mice demonstrate a significant increase cardiomyocyte cell cycle activity as determined by phosphorylated Histone H3 (pH3) staining. This seemingly contradictory result appears to be due to an underlying developmental defect in IL13 knockout hearts. Cardiomyocytes in IL13 knockout mice appeared large and disorganized. Cardiomyocytes from IL13 knockout unoperated mice showed decreased pH3 staining and had increased expression marker of hypertrophic growth such as Nppb and Nppa. Histologically, hearts from IL13 knockout mice appeared to have a dilated cardiomyopathy phenotype. Collectively our data suggests that during heart development IL13 influences proliferative versus hypertrophic growth. We surmise that following neonatal apical resection in IL13 knockout mice the significant increase in cardiomyocyte proliferation is a compensatory attempt to repair the injury, but the underlying cardiomyocyte phenotype inhibits complete regeneration. These data are the first to report a role for IL13 in normal heart development and neonatal heart regeneration.

scholarly journals Polyploidy in Cardiomyocytes

2020 ◽  
Vol 126 (4) ◽  
pp. 552-565 ◽  
Author(s):  
Wouter Derks ◽  
Olaf Bergmann
Keyword(s):  
Cardiac Injury ◽  
Physiological Role ◽  
Cell Types ◽  
Cell Number ◽  
The Body ◽  
Cardiomyocyte Hypertrophy ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Hypertrophic Growth

The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial cell loss caused by cardiac injury. In mammals, cardiac growth by cell number expansion changes to growth by cardiomyocyte enlargement soon after birth, coinciding with a period in which most cardiomyocytes increase their DNA content by multinucleation and nuclear polyploidization. Although cardiomyocyte hypertrophy is often associated with these processes, whether polyploidy is a prerequisite or a consequence of hypertrophic growth is unclear. Both the benefits of cardiomyocyte enlargement over proliferative growth of the heart and the physiological role of polyploidy in cardiomyocytes are enigmatic. Interestingly, hearts in animal species with substantial cardiac regenerative capacity dominantly comprise diploid cardiomyocytes, raising the hypothesis that cardiomyocyte polyploidy poses a barrier for cardiomyocyte proliferation and subsequent heart regeneration. On the contrary, there is also evidence for self-duplication of multinucleated myocytes, suggesting a more complex picture of polyploidy in heart regeneration. Polyploidy is not restricted to the heart but also occurs in other cell types in the body. In this review, we explore the biological relevance of polyploidy in different species and tissues to acquire insight into its specific role in cardiomyocytes. Furthermore, we speculate about the physiological role of polyploidy in cardiomyocytes and how this might relate to renewal and regeneration.

scholarly journals Functions of c-Jun in Liver and Heart Development

1999 ◽  
Vol 145 (5) ◽  
pp. 1049-1061 ◽  
Author(s):  
Robert Eferl ◽  
Maria Sibilia ◽  
Frank Hilberg ◽  
Andrea Fuchsbichler ◽  
Iris Kufferath ◽  
...  
Keyword(s):  
Heart Development ◽  
Target Genes ◽  
Cell Function ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Neural Crest Cell ◽  
Cell Types ◽  
Keratin 18 ◽  
Nuclear Factor 1 ◽  
Factor C

Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0 but little is known about the cell types affected as well as the cause of embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts, whereas the expression of 15 mRNAs, including those of albumin, keratin 18, hepatocyte nuclear factor 1, β-globin, and erythropoietin, some of which are putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in mutant livers is most likely not due to a cell-autonomous defect, since c-jun−/− fetal liver cells are able to reconstitute all hematopoietic compartments of lethally irradiated recipient mice. A developmental analysis of chimeras showed contribution of c-jun−/− ES cell derivatives to fetal, but not to adult livers, suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the reduced mitotic and increased apoptotic rates found in primary liver cell cultures derived from c-jun−/− fetuses. Furthermore, a novel function for c-Jun was found in heart development. The heart outflow tract of c-jun−/− fetuses show malformations that resemble the human disease of a truncus arteriosus persistens. Therefore, the lethality of c-jun mutant fetuses is most likely due to pleiotropic defects reflecting the diversity of functions of c-Jun in development, such as a role in neural crest cell function, in the maintenance of hepatic hematopoiesis and in the regulation of apoptosis.

scholarly journals Fosl1 is vital to heart regeneration upon apex resection in adult Xenopus tropicalis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hai-Yan Wu ◽  
Yi-Min Zhou ◽  
Zhu-Qin Liao ◽  
Jia-Wen Zhong ◽  
You-Bin Liu ◽  
...  
Keyword(s):  
Early Stage ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Heart Regeneration ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Proliferation ◽  
Neonatal Mice ◽  
Heart Injury

AbstractCardiovascular disease is the leading cause of death in the world due to losing regenerative capacity in the adult heart. Frogs possess remarkable capacities to regenerate multiple organs, including spinal cord, tail, and limb, but the response to heart injury and the underlying molecular mechanism remains largely unclear. Here we demonstrated that cardiomyocyte proliferation greatly contributes to heart regeneration in adult X. tropicalis upon apex resection. Using RNA-seq and qPCR, we found that the expression of Fos-like antigen 1 (Fosl1) was dramatically upregulated in early stage of heart injury. To study Fosl1 function in heart regeneration, its expression was modulated in vitro and in vivo. Overexpression of X. tropicalis Fosl1 significantly promoted the proliferation of cardiomyocyte cell line H9c2. Consistently, endogenous Fosl1 knockdown suppressed the proliferation of H9c2 cells and primary cardiomyocytes isolated from neonatal mice. Taking use of a cardiomyocyte-specific dominant-negative approach, we show that blocking Fosl1 function leads to defects in cardiomyocyte proliferation during X. tropicalis heart regeneration. We further show that knockdown of Fosl1 can suppress the capacity of heart regeneration in neonatal mice, but overexpression of Fosl1 can improve the cardiac function in adult mouse upon myocardium infarction. Co-immunoprecipitation, luciferase reporter, and ChIP analysis reveal that Fosl1 interacts with JunB and promotes the expression of Cyclin-T1 (Ccnt1) during heart regeneration. In conclusion, we demonstrated that Fosl1 plays an essential role in cardiomyocyte proliferation and heart regeneration in vertebrates, at least in part, through interaction with JunB, thereby promoting expression of cell cycle regulators including Ccnt1.

scholarly journals Metformin accelerates zebrafish heart regeneration by inducing autophagy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fangjing Xie ◽  
Shisan Xu ◽  
Yingying Lu ◽  
Kin Fung Wong ◽  
Lei Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systolic Function ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Systematic Evaluation ◽  
Autophagic Flux ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Clinical Value ◽  
Zebrafish Model

AbstractMetformin is one of the most widely used drugs for type 2 diabetes and it also exhibits cardiovascular protective activity. However, the underlying mechanism of its action is not well understood. Here, we used an adult zebrafish model of heart cryoinjury, which mimics myocardial infarction in humans, and demonstrated that autophagy was significantly induced in the injured area. Through a systematic evaluation of the multiple cell types related to cardiac regeneration, we found that metformin enhanced the autophagic flux and improved epicardial, endocardial and vascular endothelial regeneration, accelerated transient collagen deposition and resolution, and induced cardiomyocyte proliferation. Whereas, when the autophagic flux was blocked, then all these processes were delayed. We also showed that metformin transiently enhanced the systolic function of the heart. Taken together, our results indicate that autophagy is positively involved in the metformin-induced acceleration of heart regeneration in zebrafish and suggest that this well-known diabetic drug has clinical value for the prevention and amelioration of myocardial infarction.

Abstract 225: Coordinated Transcriptome and Cell State Dynamics of Non-myocytes in Heart Regeneration

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Hong Ma ◽  
Ziqing Liu ◽  
Yuchen Yang ◽  
Dong Feng ◽  
Yanhan Dong ◽  
...  
Keyword(s):  
Cardiac Regeneration ◽  
Cell Types ◽  
Multiple Time ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cellular Functions ◽  
Molecular Features ◽  
Functional Dynamics ◽  
Cell Diversity ◽  
Multiple Time Points

Cardiac regeneration occurs primarily through proliferation of existing cardiomyocytes, yet the regenerative response also involves complex interactions between distinct cardiac cell types including not only cardiomyocytes, but also non-cardiomyocytes (nonCMs). However, the subpopulations, distinguishing molecular features, cellular functions, and intercellular interactions of nonCMs in heart regeneration remain largely unexplored. Using the LIGER algorithm, we assembled an atlas of cell states from 61,977 individual nonCM scRNA-seq profiles isolated at multiple time points during heart regeneration in both wildtype and mutant fish. This analysis revealed extensive nonCM cell diversity, including multiple macrophage, fibroblast and endothelial subpopulations with unique spatiotemporal distributions and cooperative interactions during the process of cardiac regeneration. Genetic and pharmacological perturbation of macrophage functional dynamics compromised interactions among nonCM subpopulations, reduced cardiomyocyte proliferation, and caused defective cardiac regeneration. Furthermore, we developed a computational algorithm called Topologizer to map the topological relationships and dynamics of nonCMs during heart regeneration. We uncovered dynamic transitions between macrophage functional states and identified factors involved in mRNA processing and transcriptional regulation associated with the transition. Together, our single-cell transcriptomic analysis of nonCMs during cardiac regeneration provides a blueprint for interrogating the molecular and cellular basis of cardiac regeneration.

Abstract 15756: Vascular Guidance of Cardiomyocyte Proliferation During Growth and Regeneration

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Paige DeBeneditts ◽  
Anish Karpurapu ◽  
Kyla Brezitski ◽  
Michael C Thomas ◽  
Ravi - Karra
Keyword(s):  
Large Scale ◽  
Nearest Neighbor ◽  
Critical Role ◽  
Cell Types ◽  
Neonatal Mouse ◽  
Angiogenic Factor ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiac Growth ◽  
Multiple Cell

Introduction: Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance. Hypothesis: We hypothesized that CECs are required for CM proliferation during growth and regeneration. Methods and Results: We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express Vegfr2 . To functionally link CEC and CM proliferation, we generated Cdh5-CreER T2 ; Vefgr2 flox/flox mice to genetically delete Vegfr2 from CECs. Compared to mice with intact Vegfr2 , loss of Vegfr2 from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when Vegfr2 is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor, Vegfa can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14). Conclusions: CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.

scholarly journals Polyploid cardiomyocytes: implications for heart regeneration

Development ◽  
2021 ◽  
Vol 148 (14) ◽  
Author(s):  
Anna Kirillova ◽  
Lu Han ◽  
Honghai Liu ◽  
Bernhard Kühn
Keyword(s):  
Cellular Proliferation ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Form And Function ◽  
Differentiated Cells ◽  
New Findings ◽  
Polyploid Cells ◽  
And Function

ABSTRACT Terminally differentiated cells are generally thought to have arrived at their final form and function. Many terminally differentiated cell types are polyploid, i.e. they have multiple copies of the normally diploid genome. Mammalian heart muscle cells, termed cardiomyocytes, are one such example of polyploid cells. Terminally differentiated cardiomyocytes are bi- or multi-nucleated, or have polyploid nuclei. Recent mechanistic studies of polyploid cardiomyocytes indicate that they can limit cellular proliferation and, hence, heart regeneration. In this short Spotlight, we present the mechanisms generating bi- and multi-nucleated cardiomyocytes, and the mechanisms generating polyploid nuclei. Our aim is to develop hypotheses about how these mechanisms might relate to cardiomyocyte proliferation and cardiac regeneration. We also discuss how these new findings could be applied to advance cardiac regeneration research, and how they relate to studies of other polyploid cells, such as cancer cells.

scholarly journals Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

2020 ◽  
Author(s):  
Rebecca Ryan ◽  
Bethany R. Moyse ◽  
Rebecca J. Richardson
Keyword(s):  
Cardiac Injury ◽  
Cell Communication ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Regenerative Process ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Underlying Mechanisms ◽  
Different Cell Types

Abstract The study of heart repair post-myocardial infarction has historically focused on the importance of cardiomyocyte proliferation as the major factor limiting adult mammalian heart regeneration. However, there is mounting evidence that a narrow focus on this one cell type discounts the importance of a complex cascade of cell–cell communication involving a whole host of different cell types. A major difficulty in the study of heart regeneration is the rarity of this process in adult animals, meaning a mammalian template for how this can be achieved is lacking. Here, we review the adult zebrafish as an ideal and unique model in which to study the underlying mechanisms and cell types required to attain complete heart regeneration following cardiac injury. We provide an introduction to the role of the cardiac microenvironment in the complex regenerative process and discuss some of the key advances using this in vivo vertebrate model that have recently increased our understanding of the vital roles of multiple different cell types. Due to the sheer number of exciting studies describing new and unexpected roles for inflammatory cell populations in cardiac regeneration, this review will pay particular attention to these important microenvironment participants.

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